WO2009004141A2 - Method for preparing enantiomerically enriched n-carboxyanhydride - Google Patents

Abstract

The invention relates to a method for preparing an enantiomerically enriched N-carboxyanhydride of an amino alpha acid of the formula (IIIa) or (IIIb) : F(I) from a compound of the formula (IIa) or respectively (IIb) : F(II), wherein: R1 and R2 each represent independently an alkyl group (e.g. methyl, ethyl, isopropyl), alkenyl group (e.g. allyl), cycloalkyl group, alkyl-cycloalkyl group (e.g. -CH2-cyclohexyle), alkyl-aryl group (e.g. benzyl), aryl group; R3 is an alkyl group (e.g. methyl, ethyl, tertio-butyl) or alkyl-aryl group (e.g. benzyl); the method comprises the following steps: (i) contacting the compound of the formula (IIa) with SOCI2 in a solvent; (ii) precipitating the N-carboxyanhydride formed during step (i) using a non-solvent; (iii) recovering the N-carboxyanhydride. The method does not include any re-crystallisation nor sublimation step of the N-carboxyanhydride, and the method can be used for example in the production of (L)-N-methyl-alanine N-carboxyanhydride.

Description

 PROCESS FOR PREPARING Λ / -CARBOXYAN HYDRI OF ENANTIOMERICALLY ENRICHED

The present application relates to a process for the preparation of an enantiomerically enriched Λ / -carboxyanhydride with an alpha amino acid, more particularly (L) - carboxyanhydride or (DJ-ZV-methylalanine). also relating to a chemical intermediate which is used in the preparation of the carboxyanhydride of (L) - or (OJ-W-methylalanine.

[The technical field and the technical problem]

Amino acid β-carboxyanhydrides are acylating agents which have the advantage of not forming annoying by-products in acylation reactions. When they are enantiomerically enriched, they also allow to introduce a chiral carbon. They are therefore chemical compounds useful in organic syntheses, in particular in the case of syntheses of pharmaceutical compounds which are often syntheses with several reaction stages. However, it is necessary that these compounds have sufficient purity, in particular enantiomeric purity. The industrial process of preparation must be simpler and have a good overall performance.

The Applicant has developed a simple process for the preparation of α / -carboxyanhydride of alpha amino acid having a good overall yield and allowing access to a pure and enantiomerically enriched products. This process is more particularly applicable to carboxyanhydride of (L) - or (DJ-Λ / -methyl alanine.

[The prior art]

In Tetrahedron 1994, 50, No. 18, 5309-5322, the preparation of protégés / -carboxyanhydrides protected on the nitrogen atom by RO-C (= O) - from Λ /, Λ / -bis-alkoxycarbonyl ) amino acids and Vilsmeier-Haack SOCI ₂ / DMF reagent.

In the article "Untersuchungen ϋber Alpha-amino-N-carbonureanhydride. I, Zeitschrift fur Physiologische Chemie, Walter de Bruyter, Berlin 1925, 46, 72-90, the preparation of N-carboxyanhydrides is described but without any purification step.

In Angew. Chem. Int. Ed. 2003, 42, 5348-5351, the preparation of protégés / -carboxyanhydrides protected on the nitrogen atom by RO-C (= O) - is described in Scheme 3 referring to Tetrahedron Letters 1996, 37, 8439 but no purification step is described.

In J. Org. Chem. 1994, 59, 2437-2446, the preparation of Λ / -carboxyanhydrides is described but using another chemical reaction. In Tetrahedron 1994, 50, 30, 9051-9060, the preparation of Λ / -carboxyanhydrides from amino acids protected by tBuO-C (= O) - (BOC) and PCI ₃ is described. The use of PCI ₃ leads to the formation of phosphorus byproducts which remain combined with N-carboxyanhydride and which must be removed by a washing step with an industrially unacceptable perchlorinated solvent (CCI ₄ ).

In Journal of Chemical Society 1950, 3009-3013, the preparation of Λ / -carboxyanhydrides is conducted from a mixture of the two amino acids (D and L) protected by MeO-C (= O) - and SOCI ₂ and not from amino acid D or L. In addition, the final product is obtained after a precipitation step, a recrystallization step and a sublimation step. The calculated weight yield is 39% only.

In J. Mar. Chim. Heterocycl. 2002, 1, 44-47, the preparation of N-carboxyanhydrides is conducted from protected amino acid and POCI ₃ .

None of these documents describes or suggests the method of the invention.

[Description of the invention]

definitions used

Alkyl group: a linear or branched saturated aliphatic hydrocarbon group. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl groups. It is preferably a (C ₁ -C ₄ ) group;

Alkenyl group: an alkyl group comprising a C = C double bond;

Cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being involved in the cyclic structure. By way of examples, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;

Aryl group: an aromatic group comprising from 6 to 10 members, for example a phenyl group.

The present invention relates to a process for preparing an enantiomerically enriched Λ / -carboxyanhydride of an alpha amino acid of formula (IMa):

(NIa) from the compound of formula (IIa):

(IIa) formulas in which:

R1 and R2 denote, independently of one another, an alkyl group (eg methyl, ethyl, isopropyl), alkenyl (eg allyl), cycloalkyl, -alkyl-cycloalkyl (eg -CH ₂ -cyclohexyl), -alkyl-aryl (eg benzyl), aryl;

R 3 denotes an alkyl group (eg methyl, ethyl, tert-butyl) or -alkyl-aryl (eg benzyl); comprising the following steps:

(i) contacting the compound of formula (IIa) (or respectively (Mb)) with

SOCI ₂ in a solvent;

(ii) precipitating the Λ-carboxyanhydride formed in step (i) with a nonsolvent; (iii) recovering Λ / -carboxyanhydride.

This process does not include any recrystallization step or sublimation of the N-carboxyanhydride.

This method is applied in a similar way to the compound (MIb) from the compound (Mb):

(IMb) (Mb)

Preferably, R 3 denotes a methyl or ethyl group, even more preferably methyl because at the end of step (i), a light compound (R 3 Cl) is formed which can be easily removed.

Preferably, R 1 and R 2 denote, independently of one another, a methyl or ethyl group. More preferably, R 1 and R 2 are both methyl and the β-carboxyanhydride of the following formula (A) (or (B)) is obtained:

(A) (B) (A) is Λ-carboxyanhydride of (L) -Λ-methyl-alanine. The compound (Ma) of formula

qui est le carbamate de méthyle de la (/.)-Λ/-méthyl alanine.

which is the methyl carbamate of (/.) - / - methyl alanine.

(B) β-carboxyanhydride of (D) -β-methyl-alanine. The compound (Mb) which is the carbamate of (D) -N-methylalanine is preferably used:

Step (i)

The solvent of step (i) may be a chlorinated solvent such as dichloromethane, an alkyl or aryl ether such as, for example, tetrahydrofuran, 2-methyl tetrahydrofuran or 1,4-dioxane, a aromatic solvent such as for example toluene, xylene, trifluoromethylbenzene, a ketone such as for example acetone, methyl isobutyl ketone, methyl ethyl ketone. A mixture of two or more of these solvents can also be used.

1 to 3 equivalents of SOCI _{2 are} generally used relative to the compound (IIa) (or (Hb)).

The reaction is conducted at a temperature between -10 and 5O ⁰ C, preferably between 0 C and 3O ⁰ ₁ even more preferably between 20 and 30 ° C. The reaction time is generally between 30 and 60 min.

Step (ii)

Precipitation of the β-carboxyanhydride formed in step (i) is carried out using a non-solvent. Advantageously, a liquid alkane (n-heptane or octane) or a petroleum fraction (petroleum ether, for example) is used. The N-carboxyanhydride can first be concentrated by removing a portion of the solvent from the reaction of step (i).

It is possible to use a solvent / non-solvent pair, a chlorinated solvent and a liquid alkane or a petroleum cut, in particular the dichloromethane / n-heptane couple described in Example 2. Step (iii)

Λ / -carboxyanhydride can be recovered simply by filtration / drying. This is one of the advantages of the process of the invention not to require a recrystallization step or sublimation to obtain sufficient purity and good performance. The advantage of using a liquid alkane in step (ii) is to be able to dry the Λ-carboxyanhydride easily.

Preparation of the compound of formula (Ha) or (Ub)

The compound of formula (IIa) (or (Mb)) may be prepared according to the following reaction (optionally during a step preceding step (i)):

nt selon ) en présence d'une base. La base peut être par exemple un carbonate, un bicarbonate ou un hydroxyde d'un métal alcalin. Une base préférée est NaOH.(or else

according to) in the presence of a base. The base may be for example a carbonate, a bicarbonate or an alkali metal hydroxide. A preferred base is NaOH.

This reaction can be carried out in a solvent which can be for example water or one of the solvents mentioned above. The reaction is conducted at a temperature of between 0 and 5 ° C. The duration of the reaction is generally between 5 and 6 hours. Preferably, a CICO ₂ R 3 / (IIa) molar ratio (or (Hb)> 1.9 is used.) Preferably, a base / (IIa) (or (Nb)> 2 molar ratio is also used.

The method of the present invention makes it possible to obtain (whether the process includes the reaction preceding step (i) or not) a Λ / -carboxyanhydride in a simple manner, with a good yield (> at the yield disclosed in Journal of Chemical Society 1950) and good purity. In particular, it does not require any recrystallization or sublimation step. The cyclization of step (i) preserves the integrity of the asymmetric center and makes it possible to obtain an enantiomerically enriched product (no epimerization).

[Examples]

Those skilled in the art will be able to draw advantageously from the conditions disclosed in the two examples which follow. Ex 1: Preparation of (S) -2- (methoxycarbonyl-methyl-amino) -propionic acid)

In a bicolor of 250 ml under nitrogen atmosphere are successively charged: 10 gr (97 mmol) of (L) -Λ-methyl-alanine, then 200 ml of a 1 M aqueous solution of NaOH (200 mmol, 2, 06 eq.). The white suspension thus obtained is stirred until complete dissolution (approximately 30 minutes). This solution is cooled to about 3 ° C. using a water / ice bath, and under vigorous stirring (about 750 rpm), 15 ml of methyl chloroformate (192 mmol, 1.98 eq.) are added in about 30 minutes using a 50 ml dropping funnel. The biphasic medium thus obtained is stirred at ^30.degree .

After 6 hours, the temperature of the reaction medium is raised to about 20 ° C by removing the ice / water bath, and the pH of the reaction medium is brought to about 1 (measured with a pH paper) to using 37% aqueous HCl. This aqueous phase is then extracted with 3 times 50 ml of AcOEt. The organic phases are combined, washed with 50 ml of demineralised water and then dried over approximately 10 g of anhydrous MgSO ₄ . The medium is filtered on sintered glass, then the filtrate is concentrated to dryness in vacuo (bath temperature at about 35 ° C., vacuum of about 40 mbar). 13.4 g (86%) of product are thus obtained in the form of a colorless viscous oil.

structural analyzes: LC-MS-DAD-ELSD: 160 (-) = (MH) (-), 162 (+) = (M + H) (+); ¹ H NMR (DMSO d ⁶ at 400 MHz): for this batch, a 60-40% mixture of conformers is observed, with: 1.31 (d, J = 7.5 Hz, 3H); 2.78 (s, 3H); 3.58 (s, 1, 2H); 3.60 (s, 1, 8H); 4.50 (qr, J = 7.5 Hz, 0.4H); 4.58 (q, J = 7.5 Hz, 0.6H); 10.7 (spread m, 1H).

Chiral column gas chromatography analysis shows that the enantiomeric excess of the methyl carbamate of Λ-methyl alanine is> 99%. The conditions of the chromatographic analysis are given below: RT-Gammadex column (30 m / 0.25 mm / 0.25 μm); isothermal 120 ^° C. (3 min), then 5 ° C./min at 180 ^° C., isothermal at 18 ^° C. (3 min); split injection 1: 25; helium carrier gas at 1.8 ml / min; FID detection; 2 mg / ml solution in CH ₂ Cl ₂ , esterification with 0.2 M TMSH. Under these conditions, the methyl carbamate of (L) -Λ-methyl-alanine has a retention time of tr = 8.8 min. . The other enantiomer, the methyl carbamate of (D) -Λ / -methyl alanine has a retention time tr = 8.5 min. Ex 2: Preparation of (S) -3,4-dimethyl-1,3-oxazolidine-2,5-dione

1 g (6.2 mmol) of the product obtained above is dissolved in 3 ml of CH ₂ Cl ₂ , stirred for 5 minutes at approximately 20 ⁰ C, then treated with SOCI ₂ (500 μl, 1.1 eq.) . The reaction medium is then heated to about 30 ° C, and the heating is maintained for about 30 min. The reaction medium is then concentrated to about 1.5 volume, and still stirring, 10 ml of n-heptane are added. The white mass thus obtained is then cooled to about -20 ° C, and stirred for 1 hour at this temperature. The suspension is then filtered on sintered glass, the solid is washed with 3 times 3 ml of n-heptane. After drying in air for 2 hours, the product (700 mg, 87.4%) is obtained as white needles.

structural analyzes: ¹ H NMR (DMSO d ⁶ at 400 MHz): 1.39 (d, J = 7.5 Hz, 3H); 2.83 (s, 3H); 4.40 (g, J = 7.5 Hz, 1H).

Chiral column gas chromatography analysis shows that the enantiomeric excess of (S) -3,4-dimethyl-1,3-oxazolidine-2,5-dione) is> 99%, and no epimerization occurred under cyclization conditions. Conditions for gas chromatography: RT-Gammadex column (30 m / 0.25 mm / 0.25 μm); initial temperature 180 ° C then 5 ° C / min at 220 ⁰ C, isothermal at 180 ⁰ C for 5 min; split injection 1: 25; helium carrier gas at 1.8 ml / min; FID detection; 2 mg / ml solution in CH ₂ Cl ₂ . Under these conditions, (S) -3,4-dimethyl-1,3-oxazolidine-2,5-dione has a retention time of tr = 8.4 min. The other enantiomer, (R) -3,4-dimethyl-1,3-oxazolidine-2,5-dione) has a retention time of tr = 8.7 min.

The overall yield calculated from the starting (L) -Λ-methyl-alanine is therefore 86% x 87.4% or 75%. This yield is higher than that obtained in Journal of Chemical Society 1950.

Claims

claims 1. Process for preparing an enantiomerically enriched Λ / -carboxyanhydride of an alpha amino acid of formula (INa) or (HIb):

(IMa) (MIb) from the compound of formula (Ma) (or respectively (Mb):

(IIa) (Mb) formulas in which: R1 and R2 denote, independently of one another, an alkyl, alkenyl, cycloalkyl, alkyl-cycloalkyl, alkyl-aryl or aryl group; R3 denotes an alkyl or alkyl-aryl group; comprising the following steps: (i) contacting the compound of formula (Ma) (or respectively (Mb)) with SOCI ₂ in a solvent; (ii) precipitating the Λ-carboxyanhydride formed in step (i) with a nonsolvent; (iii) recovering Λ / -carboxyanhydride. and not including any recrystallization step or sublimation of N-carboxyanhydride. 2. The process of claim 1 wherein R3 is methyl or ethyl. 3. Method according to one of claims 1 or 2 wherein R1 and R2 denote, independently of one another, a methyl or ethyl group. 4. The method of claim 1 wherein R1, R2 and R3 denote a methyl group. 5. Process according to any one of claims 1 to 4 wherein the compound of formula (IIa) (or (Mb)) is prepared according to the following reaction: (or respectively)

t according to) in the presence of a base. 6. The method of claim 5 wherein the reaction is a step preceding step (i). 7. Process for the preparation of the enantiomerically enriched β-carboxy-aminyanide of formula (A) or (B):

(A) (B) comprising the following steps: (i) contacting the compound of formula

(C) or respectively (D) with SOCI ₂ in a solvent; (ii) precipitating the Λ-carboxyanhydride formed in step (i) with a nonsolvent; (iii) recovering Λ / -carboxyanhydride; and not including any recrystallization step or sublimation of N-carboxyanhydride. 8. A method according to one of claims 1 to 7 wherein the reaction of step (i) is conducted at a temperature between -10 and 50 ⁰ C, preferably between O and 3O ⁰ C, more preferably between 20 and 30 ° C. 9. Method according to one of claims 1 to 8 wherein the reaction of step (i) is conducted with 1 to 3 equivalents of SOCI ₂ relative to the compound (Ma) (or respectively (Mb) ) or (C) (or respectively (D)) 10. Method according to one of claims 1 to 9 wherein the non-solvent of step (ii) is a liquid alkane or a petroleum cut. 11. A method according to one of claims 1 to 10 wherein is used as the solvent / non-solvent pair a chlorinated solvent and a liquid alkane or a petroleum pair, preferably the dichloromethane / n-heptane pair. The process according to any one of claims 1 to 11 wherein the recovery of the β-carboxyanhydride of step (iii) is filtration / drying. 13. Compound of formula: